The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy

• Published in: Cellular & molecular immunology Vol. 13; no. 1; pp. 73 - 81
• Main Authors: Li, Yan-Hong, Zhou, Wen-Hui, Tao, Yu, Wang, Song-Cun, Jiang, Yun-Lan, Zhang, Di, Piao, Hai-Lan, Fu, Qiang, Li, Da-Jin, Du, Mei-Rong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2016; Nature Publishing Group
• Subjects: Abortion, Spontaneous - genetics; Abortion, Spontaneous - immunology; Abortion, Spontaneous - pathology; Adult; Animal models; Animals; Antibodies; Antibodies, Neutralizing - pharmacology; Biomedical and Life Sciences; Biomedicine; Coculture Techniques; Cytokines; Decidua; Decidua - immunology; Decidua - pathology; Female; Fetuses; Galectin-9; Galectins - genetics; Galectins - immunology; Gene Expression Regulation; Hepatitis A Virus Cellular Receptor 2; Humans; Immune response; Immune Tolerance; Immunological tolerance; Immunology; Inflammation; Interleukin-4 - genetics; Interleukin-4 - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lymphocytes T; Maternal-Fetal Exchange - immunology; Medical Microbiology; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Inbred CBA; Mice, Inbred DBA; Microbiology; Miscarriage; Natural killer cells; NK细胞; Perforin; Perforin - genetics; Perforin - immunology; Phenotypes; Pregnancy; Primary Cell Culture; research-article; Signal Transduction; Trophoblasts; Trophoblasts - immunology; Trophoblasts - pathology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vaccine; 功能调节; 早孕; 炎性细胞因子; 界面; 肿瘤坏死因子; 自然杀伤细胞; 通路; NK cells; galectin-9/Tim-3; cytotoxicity; pregnancy; Th2
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/cmi.2014.126

Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.